Maoecrystal V

13 December 201038,995 views61 Comments

Yep, I didn’t quite manage a new post – blame it on the ‘flu. But I also don’t want this article on Maoecrystal V to fall between the cracks. I think it’s awesome that this target has been conquered, but I’m not sure that this paper is the fullest explanation of the science used to do it.

Me hates to nitpick; however I understand in your discussion of Scheme 2, the resulting Rh-carbenoid species inserts into the cyclohexyloxy O-H bond, and not the phenolic one, as this one’s suitably protected as the MOM ether (or acetal, for what it’s worth…)

I’d personally like to work on Aphanamolide, the new limonoid in Org. Lett. See link in “What I’m Reading” section above, top-right… It has a few bits and pieces of the evil azadirachtin, my postdoctoral nemesis…

The OL last year disclosing the strategy is nearly identical to Baran’s article in the same issue of OL (and cited in the JACS paper). I understand that two groups can have the same idea independently, but what I find disturbing is that one of the PIs on this synthesis was a postdoc in Baran’s lab while Baran was working on Maoecrystal (see the footnote in Baran’s OL). Its pretty hard to escape the conclusion that he left Baran’s group knowing the strategy, rushed to repeat the work, and then quickly published in OL so that he would be the first to publish.

So a few things I wanted to bring up regarding this molecule. First some chemistry for those who are actually interested in that sort of discussion. I think the Me4NBH4 reduction of the ketone to deliver hydride from the more hindered face deserves some comment. In the paper, they say, “We attribute this diastereoselectivity to the directing and accelerating effect of the cationic-pi interaction between between ammonium salt and the phenyl ring…” I simply do not buy this argument. The cation-pi interaction would be present even with NaBH4. Granted the overall effect would probably be lower since the positive charge is actually centered on the protons in the tetramethylammonium borohydride, but even if the cation pi interaction were in effect, it would be INCREDIBLY crowded along the top face, and it’s even less likely that the hydride could be delivered from that face. Second, this type of reagent is exceptionally non-coordinating, so even if cation-pi were in effect, there would be no reason to assume that the hydride was tagging along. Along these same lines, Evans showed some years ago that this type of reagent (in particularl the triacetoxyborohydride variant) is incredibly good at being directed by alcohols or ethers. In this case, the solvent is methanol which is known to form the trimethylborohydride in situ, and the MOM ether on the aromatic ring is almost perfectly poised to direct this hydride source from the top face of the molecule.

Second, regarding Anon’s claim that this is “based on a stolen idea,” your judgement must be clouded because this synthesis is NOTHING like the original OL disclosure. You can say what you want about the OL’s similarity to Baran’s approach, but there are a few points that I think are worth mentioning. First, the idea of an intramolecular Diels-Alder to establish the core structure is not ground breaking. Essentially EVERY group has had this same retro, and it’s really not that far-fetched. Second, this new approach has absolutely NOTHING to do with Baran’s initial report (or theirs for that matter). If you read the paper, you realize that approach could not be used to fashion the complete skeleton b/c it was too strained to make one of the last bonds. This is why the Rhodium insertion is so fantastically clever. It solves the core issue of how to establish all of the ring systems. Baran absolutely did not allude to this in his OL, and as such, the problem was really solved by their group.

is there anything that isn’t “stolen”? every day that you don’t float away from the earth, does someone say that you stole gravity? just do your work, learn, be thankful to those suffered the same kind of anguish as yourself in understanding chemistry, and realize that science is greater than yourself. in other words, just chill. no one person ever did anything alone. saying ideas are stolen is a slippery slope. i’m not trying to be a jerk, and am not experiencing any angst as i write this, rather i’m urging those who are prone to destructive thoughts to step back and realize your place.

such a neat looking molecule. quite impressive synthesis. there things that surprised/confused me –
-hinging the synthesis on a late-stage hydrogenation of a C=C to C-C, in the presence of another C=C, using lindlar’s catalyst?
-no compound “2d” isolated? (the forth assumed IMDA product)
-interesting allylic oxidation used instead of SeO2?

A Chinese research group who this year alone has completed quite a few other nice targets beats the whole synthetic community to Maoecrystal and all of a sudden it’s only because they stole it from Phil Baran? You’re honestly trying to convince me that the guy who made Vinigrol and Palau’amine in the same year would not be able to implement whatever his master plan for Maoecrystal faster than these guys? I had heard of a Baran fan club, but this is waaaay too much IMO.

That Deslongchamps Ryanodol work is just amazing. Well-written papers, beautiful work. While I agree with the premise that modern synthetic techniques might allow for a “shorter” route to ryanodol, I find it hard to believe a more elegant route or subsequent paper possible. Furthermore, is it “worth doing”?

Obviously “CantRead” was being sarcastic. His/her opinion aside, I still say this is nothing special. Some have differing opinions and that is good – that’s what we should be doing. “CantRead” wants to express their opinion in the manner with which they did – doesn’t detract from my initial opinion (and continuing opinion) of this synthesis of – meh. Nothing special, nothing of note here. Just another example of being able to synthesize anything.

I have a few questions I was concerned about, the first one being the Lindlar Reduction of one olefin over the other how do you explain the selectivity? The other reaction was the Rh assisted O-H insertion, why not at the phenol.

Just read the Begu Sezen case (ya…C&E is a bit late in this part of the world). Anyways, what happens to Sames..is he off the hook? Shouldnt the university fire him first? I heard him boasting about his work in a conference where he said “we did it…’ and now its “Bengu did it”. He should add, I was just writing a paper…ooops did she get charged for plagarism….I had nothing to do with it then…I just happened to be around.
If the work was real and repeatable, today we would have been calling it “Sames C-H activation” and now its Bengu’s fraud!

however the “mine” vs “hers” observation is correct
some labs avoid this type of incident by telling a student or post-doc not on the project in question to independently verify representative results PRIOR to publication, this may not be fail safe but would appear to be valuable – particularly in cases of egregious fraud where it’s not a matter of 50% vs 85%, but a matter of whether it works at all

both labs i’ve been involved in have done this type of “independent verification.” it also lets the person developing the method know if there is anything unclear about the reaction process, from set-up to work-up. and, it doesn’t really take much effort.

So, you’re saying completing a synthesis of however obscenely complex molecule without gold catalysis, or any other fancy “flavour-of-the-month” chemistry is not good enough for scientific community to appreciate it?

That would have been a joke if this sequence was not targeted towards maitotoxin. However, since KCN group is targeting a structure as huge as maitotoxin I think its ok. Who else if going to make that thing and how different can it be than the current route? This synthesis if completed will be counted as a one of the great feats in organic syntehsis…I think.

Making maitotoxin is a waste of time/resources, nobody is gonna check that synthetic route, therefore, you’ve gotta just trust the KCN group & its chief…..but would you? Instead, developing some new practical methodologies is what everyone should be doing.

If you start with the ACS 1996 settings, then make all the bonds thicker, and make all of the atoms bold, you start to get something that looks a lot better. Then just start drawing things in perspective, and you’ve got MacMillan- or Baran-looking structures. Then publish it in a journal where most of the bonds disappear when you view it online so it looks like a bunch of floating atoms…

Okay, I’ll be the first one…really, this is in Nature?!? The Toste work is nothing more than Org. Lett. Nature is really stretching its bounds to get chemistry in there; at least be something worthwhile…

Quote: “Starting with a rather unconventional coupling, the group quickly built the first quaternary stereocentre. This oxidative coupling reaction is unfortunately not discussed in any detail, and neither is the synthesis of the aryllead intermediate, so we’ll have to wait for a full paper to understand their rationale for using such exotic – and presumably toxic – conditions (figure 1).”

For a discussion of this method see Organic Syntheses, Coll. Vol. 7, p.229 (1990); Vol. 62, p.24 (1984). Being an Org Syn method we can assume it is fairly reproducible. Anyway, check out the discussion section for more info:

[…] member of that family that I’e blogged – the seminal synthesis of Maoecrystal V made my December 2010 column in Chemistry World. I remember when I wrote that piece that the pseudo-3D structure used to represent the target […]

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